4-chloro-pregnadiene-steroids and method of making the same



United States Patent Office 3,549,671 Patented Dec. 22, 1970 US. Cl.260-3974 4 Claims ABSTRACT OF THE DISCLOSURE 4 chloro 1,20t. methylene Apregnadiene 17a.- ol-3,20-dione and the 17-esters thereof.

An example is 4-chloro-l,2oL-methylene-A-pregnadiene-17a-o1-3,20-dione-17-acetate.

The compounds have a high progestational and ovulation suppressingaction with only very minor antiandrogenie side effects.

BACKGROUND OF THE INVENTION Various steroids have become known having amore or less marked progestational action. However, most of thesecompounds require injection to be elfective. Furthermore, they usuallyhave undesirable antiandrogenic side effects.

SUMMARY OF THE INVENTION It is therefore an object of the presentinvention to provide for compounds having a strong progestational andovulation suppressing action in case of oral application.

It is a further object to provide for such compounds which, togetherwith their progestational action and the suppression of ovulation, haveonly a very minor antiandrogenic side effect.

These objects are met by compounds selected from the group consisting of4-chloro-l,2a-methylene-A -pregnadiene-17oc-ol-3,20-dione and its17-esters.

The compounds may .be made by any one of the following processes:

(a) A corresponding 63-hydroxy-7a.-chloro-A -3-ketosteroid may bereacted with an acid chloride in the presence of an organic base, or

(b) A corresponding 6B,7a-dichloro-A -3-ketosteroid may be reacted withan alkali halide in the presence of a basic solvent, and preferably uponaddition of an alkali or alkaline earth carbonate, or

(c) A corresponding A -3-ketosteroid may be chlorinated in the4-position, or

(d) A corresponding 4-chloro-A -3-ketosteroid may be methylenated in the1,2-position.

Following any one of these reactions, 21 free 17-hydroxy group that maybe present in the product may then be esterified, or an esterifiedl7-hydroxy group present in the product may be subjected tosaponification.

DESCRIPTION OF THE PREFERRED EMBODIMENTS As stated, the compounds of theinvention are either the 4-chloro-1,Zoe-methylene-A-pregnadiene-17a-o1-3,20- dione or the 17-esters thereof. Preferredesters are the acylates of carboxylic acids having up to 15 carbonatoms, particularly lower and intermediate aliphatic carboxylic acids.The acids may also be unsaturated, branched polycarboxylic acids or theymay be substituted in conventional manner, for instance by amino,hydroxyl or carboxyl groups, or by halogen atoms. If it is desired toobtain water-soluble compositions, it is preferred to use esters ofinorganic acids, such as those of sulfuric or phophoric acid.

Regarding the processes above summarized, it should be noted that thesplitting off of water in the process listed in the Summary at (a) canbe effected in conventional manner upon simultaneous migration of thechlorine atom from the 711- into the 4-position. The water eliminationcan be effected, for instance, with an acid chloride, such asmethane-sulfonic acid-chloride, in the presence of an organic base.Preferably, elevated temperatures are employed to shorten the reactiontime. The reaction is complete usually after 1 to 5 hours attemperatures between 50 and C.

Regarding the process listed in the Summary at (b), it is noted that thehydrogen chloride elimination and rearrangement of the 7-chlorine atominto the 4-position can likewise be effected in conventional manner.According to a preferred embodiment, reaction is effected between the6,7-dichloro-product in a basic solvent, preferably dimethylformamide,with an alkali-halide such as lithiumchloride or -brornide at elevatedtemperature. Preferably, the reaction takes place in the presence of analkalior alkaline earth-carbonate, such as lithiumor calciurncarbonate.The reaction time depends on the reaction temperature. For instance, atC. the reaction time is about 2 hours. The reaction is preferablycarried out upon exclusion of the oxygen of the air, for instance 'byuse of a nitrogen atmosphere.

The chlorination of the A -dienone according to the process abovesummarized at (c) is likewise effected in conventional manner. Forinstance, the 4-chloro-substitution is carried out under the action. ofelemental chlorine in the presence of a lower carboxylic acid and usingan organic base as solvent, the temperature perferably being between -30and +30 C.

Preferred organic bases are dimethylformamide and pyridine. However,lutidine, collidine, aniline, diethylamine, etc. may also be used.

The methylenation of the A -3-ketone in the process summarized above at(d) is carried out in conventional manner, for instance by reacting al-mol equivalent of dimethylmethylenesulfoniumoxide with the unsaturatedketone at a temperature between -40 and +100 C., and preferably at roomtemperature. Dimethylmethylenesulfoniumoxide can be liberated in areaction mixture of trimethylsulfoxonium salts, such as halides,perchlorates or methylsulfates, with bases such as sodiumhydride orsodiumor potassium-hydroxide or -alcoholate. The reaction is effected inan aprotonic solvent or solvent mix ture. A purification operation mustfollow, since the desired LZwmethyIene-cOmpOund will be contaminatedwith the 1,Za;6,7,B-dimethylene-compound even when using stoichiometricamounts. The methylene-compounds are preferably converted toiodomethyl-compounds for the purpose of the chromatographic separation.The reaction with hydrogeniodide in formic acid at room temperatureleads to 4-ch1oro-1u-iodomethyl-A -3-ketosteroid and4-chlor0-7fi-iodomethyl 1,2a methylene-A 3-ketosteroid. The1,2a-methylene-group is reconverted, for instance by heating of thelot-iodomethyl-compound in collidine, after separation of the4-chloro-1ot-iodomethyl-A -3-ketosteroid.

The compounds of the invention are valuable pharmaceutical products.They have a surprisingly strong progestational and ovulation suppressingaction in the case of oral applications, with only very minorantiandrogenic side effects. This will be clearly apparent from thefollowing table, where a preferred embodiment, 4-chloro-1,2a-methylene Apregnadiene-17ot-ol-3,20- dione-acetate (Compound I) is compared withother progestational compounds of high efiiciency (Compounds II andIII).

For the purpose of the tests, the progestational action was determinedas usual by ascertaining the limit value in the peroral Clauberg Test,that is, the minimum amount necessary to obtain an afiirmative action.

The ovulation suppression was determined by tube inspection. The tablelists as WD that daily dose which results in omission of the ovulationwith 50% of the animals (female rats).

TABLE I Progestetional action unit Ovulation suppresvalue sion WDCompound The main application of the compounds of the invention is inthe treatment of the following gynecological disorders: primary andsecondary amenorrhea of longer duration, cycle irregularities in thecase of insuflicient yellow body function, endometriosis, hypoplasia ofthe uterus, premenstrual complaints and mastopathy. A treatment with thenew compound-s is also indicated if it is desired to avoid conception.

The dosage depends on the seriousness of the specific case. In general,a daily dose of between 1 and 50 mg. of active compound may be used.

The making of the pharmaceutical products may be effected in theconventional manner by incorporating the active materials with suitablecarrier substances. Carrier substances may be organic or inorganicmaterials which are suitable for either enteral or parenteralapplication and which do not enter into reaction with the new compounds,such as, for instance, water, alcohols, vegetable oils,polyethyleneglycols, lactose, starch, talcum, gelatin, magnesiumstearate, sodium laurylsulfate, etc.

The new compounds can be used in the form both of orally or parenterallyadministered pharmaceuticals. The content of active substance should be,for instance in the case of capsules or tablets, about 1 to mg. perunit, in case of aqueous solutions for oral applications about 0.5 to 2mg. per 1 ml., and in case of oily solutions for intramuscular injectionabout 1 to mg. per 1 ml.

The following are preferred examples of specific compoundings:

(1) Gelatin capsules having each 5 mg. of active substance Compositionfor one capsule: Mg. 4 chloro 1,2a methylene-A -pregnadiene-17ot-ol-3,20-dione-l7-acetate (finely reduced to a particle size 2-8 12,with a few particles 16,11.) 5 Lactose 200 4 The substance is placed inthe conventional manner into hard gelatin two-piece capsules.

(2) Tablets containing 15 mg. active substance (3) Preparations that canbe administered as drops, 1 ml.=2 mg. of active substance (1 ml.corresponds to 30-35 drops) Composition for 100 ml.:

4 chloro 1,2ot methylene-A -pregnadiene- 17ot-ol-3,20-dione-l7-acetatemg 200 Ethyl alcohol ml 20 Propyleneglycol ml 25 Plus water to make up100 ml.

(4) Oily solutions for intramuscular injection 1 ml.=2 mg. activesubstance Mg. 4 chloro-1,2a-methy1ene-A -pregnadiene-17a-ol-3,20-dione-17-acetate 2.0 Benzyl alcohol 20.0 Sesame oil 905.9

The following examples will illustrate the invention without anyintention of limitation:

(A) Processes for making the starting products7u-chloro-1,Za-methylene-A -pregnene-6B,17a-diol-3,20-dione-17-acetate.-A solution of 5.0 g. 1,2a-methylene- Apregnadiene-l7ot-ol-3,20-dione-acetate in 250 ml. dioxane was reactedwith 20.0 g. N-chlorosuccinimide, 135 ml. water and 12.5 ml. perchloricacid. The reaction was complete after minutes at room temperature. Themixture was poured into sodium sulfite-containing water, was subjectedto suction, and the precipitate was taken up in methylenechloride,washed with water and dried over sodium sulfate. The solvent wasevaporated in vacuum and the residue was recrystallized frommethylenechloride/ diisopropylether. There was obtained 2.24 g.7a-chloro- 1,Za-methylene-A -pregnene 65,17ot diol-3,20-dione-17-acetate, M.P. 239239.5 C. UV: e =12,90O.

6fl,7a-dichloro-1Jot-methylene-M-pregnene-17a-ol-3,20- dione-acetate.5.0g. 1,Za-methyIene-A -pregnadiene- 17u-ol-3,ZO-dione-acetate wasdissolved in 65 ml. absolute trichloroethylene and reacted with asolution of 9.28 g. chlorine in ml. absolute carbon tetrachloride. Aftera reaction time of 2 hours at 20 C., the reaction mixture was dilutedwith chloroform and successively washed with dilute sulfuric acid,sodium hydrosulfite solution, sodium bicarbonate and water. The residuewas subjected to chromatography over silica gel after drying andconcentration by evaporation. After recrystallization from ethylacetate, 1.30 g. GflJa-dichloro-1,2a-methylene-A-pregnene-17a-ol-3,20-dione-acetate was obtained, with a melting-pointbetween 254 and 256 C. UV: e =l2,6()0.

(B) Example I A solution of 200 mg. 7a-chloro-1,2a-methylene-Apregnene-6B,l7a-diol-3,20-dione-17-acetate in 2.8 ml. dimethylformamidewas reacted with 0.8 ml. pyridine and 0.4 ml. methanesulfonic acidchloride and heated for 3 hours to 85 C. The mixture was subjected toprecipitation with water, followed by suction, washing with water anddrying in vacuum. The crude product was purified by means of thin layerchromatography. After recrystallization from acetone/hexane, 50 mg.4-chloro-l,2a-methylene-A -pregnadiene-17a-ol-3,20 dione-acetate wasobtained with a melting-point between 256 and 256.5 C. UV: 6 95:18,500.

Example II 2.26 g. 6fl-7u-dichloro-1,2a-methylene-A-pregnene-17ozol-3,20-dione-'acetate, 1.11 g. lithiumcabonate, 1.3 g.lithiumbomide and 50 ml. dimethylfomamide were stirred for 2 hours undera current of nitrogen at 140 C. The product was subsequently taken up inether, washed with dilute sulfuric acid and water, dried, and evaporatedin vacuum to dryness. The residue was subjected to chromatography oversilica gel. After recrystallization from ethyl acetate, there wasobtained 450 mg. 4-chloro-1,Za-methyIene-Apregnadiene-17u-ol-3,20dione-acetate, with a meltingpoint between 248and 250 C. UV: e =l7,500.

Example III 5.0 g. lion-methylene A pregnadiene-17a-ol-3,20- dioneacetate was dissolved in 200 ml. dimethylformamide and reacted with asolution of 930 mg. chlorine in 14.25 ml. propionic acid. The mixture,after a reaction time of 18 hours at -15 C., was stirred into ice water,whereupon the precipitate was removed by suction and taken up withmethylene-chloride. The organic phase was washed with a sodiumbicarbonate solution and water, dried, and evaporated to dryness invacuum. The residue was subjected to chromatography over silica gel.After recrystallization from ethyl acetate, there was obtained 600 mg.4-chloro-1,2u-methylene-A -pregnadiene-17aol-3,20-dione-acetate, with amelting-point between 250 and 251 C. UV: e =17,900.

Example IV 240 mg. sodium hydride (in the form of a 50% oil suspension)and 1.1 g. trimethylsulfoxonium-iodide were dissolved in 17 ml.dimethylsulfoxide upon introduction of nitrogen and stirring. There wasthen added 20 ml. abs. tetrahydrofuran and the solution was chilled toC. 1.5 g. 4-chloro-A -pregnatriene-l7m-ol-3,20-dione was then added. Theproduct was then subjected to precipitation in acetic acid ice waterafter 3 hours stirring at room temperature. The precipitate was removedby suction, taken up in methylenechloride, washed with a sodiumbicarbonate solution and water and dried.

The separation of 4-chloro-1a,2u;6,B,7B-dimethylene-Apregnene-17ix-o1-3,20-dione which occurred as a by-prodnet in an amountof between 5 and was effected by reacting the reaction product withhydriodic acid in formic acid at room temperature. The components4-chloro-7 6- iodomethyl-lulu-methylene 4 pregnene-17a-ol-3,20- dioneand 4-chloro-1a-iodomethyl-A -pregnadiene-17o:- ol-3,20-dione wereseparated by chromatography over silica gel with 20% acetone/hexane. Thesecond of these components was stirred into 5 ml. collidine for 20 hoursat 140 C. upon introduction of nitrogen in order to form the1a,2u-cyclopropane ring. The reaction product was then stirred intohydrochloric acid ice water and extracted with ether. The ether phasewas washed with sodium bicarbonate and water. After recrystallizationfrom acetone/hexane, there was obtained 425 mg. 4-Ch1OIO-loc,20t-

6 methylene A pregnadiene-17a-ol-3,20-dione, with a melting-pointbetween 246 and 251 C. (acetone/ hexane). UV: e =17,5O0.

Example V 1.5 g. 4-chloro-1a,Za-methyIene-A-pregnadiene-l7aol-3,20-dione was stirred into 16 ml. glacial aceticacid with 10 ml. glacial acetic acid anhydride and 800 mg.p-toluenesulfonic acid. The stirring was carried out for 17 hours atroom temperature upon introduction of nitrogen. The reaction solutionWas poured into ice Water. The precipitate was removed by suction,washed with water and dried. After chromatography over silica gel with15- 20% acetone/hexane, there was obtained 750 mg. 4-chloro-111,2a-methyIene-A -pregnadiene 17oz o1 3,20- dione-l7-acetate,M.P. 258259 C. (acetone/hexane). UV: 29 =18,000-

Example VI 150 mg. 4-chloro-1a,2amethylene-A -pregnadiene-17wol-3,20-dione-17-acetate was allowed to stand for 3 days at roomtemperature in 3.5 ml. caproic acid anhydride with 50 mg.p-toluene-sulfonic acid. The reaction mixture was reacted with a littlepyridine and subsequently distilled in a current of steam. The aqueousphase was then ex tracted with ether. The ether phase was dried oversodium sulfate and concentrated to dryness in vacuum. The purificationwas effected by thin layer chromatography. There was obtained 70 mg.4-chloro-1a,Zm-methyIene-M -pregnadiene-17u-ol-3,20-dione-17-capronatein the form of an Oil- UV: 6295:

Example VII 200 mg. 4-chlor-la,2a-methylene-A -pregnadiene-17u-ol-3,20-dione-17-acetate was stirred for 15 hours at roomtemperature into 30 ml. methanol containing 3.0 m1. 1 N-sodiumhydroxide. The reaction solution was neutralized with acetic acid andsubstantially concentrated in vacuum. The precipitate obtained bypouring into ice Water was removed by suction, washed neutral and dried.After recrystallization from acetone/hexane there was obtained mg.4-chloro-1a,2amethylene-A -pregnadiene- 17oc-0l-3,20-di0l16 having amelting point of 245-250 C UV: E296=17,600'

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constituteessentialcharacteristics of the generic or specific aspects of thisinvention and, 'therefore, such adaptations should and are intended tobe comprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims.

What is claimed is:

1. A. compound selected from the group consisting of4-chloro-l,2u-methylene A pregnadiene-17a-o1-3,20- dione and a17-carboxylic acid ester thereof having from 1 to 15 carbon atoms in theacyl residue.

2. The compound of claim 1 which is 4-ChlOI0-1,2amethylene-A-pregnadiene-17a-ol-3,20-dione.

3. The compound of claim 1 which is 4-chloro-1,2amethylene-A-pregnadiene-17a-0l-3,20-dione-17-acetate.

4. The compound of claim 1 which is 4-ChlOfO-1,2ozmethylene-M-pregnadiene 17a-ol-3,20-dione-l7-capronate.

No references cited. HENRY A. FRENCH, Primary Examiner US. Cl. X.R.424-443

